FP-1039 is a ligand trap that is designed to selectively intervene in fibroblast growth factor (FGF) signaling. FGFs are a family of 22 related extracellular proteins called ligands that normally regulate cell proliferation and survival in humans. They act by binding to and activating FGF receptors (FGFRs), which are cell surface proteins that transmit growth signals to cells. Certain FGFs promote growth of multiple solid tumors by binding and activating FGFRs.
In certain tumor types there is amplification of the FGFR1 gene, which results in over-expression of the FGFR1 protein on the surface of the tumor cell. Also, tumors sometimes overexpress fibroblast growth factor ligands for FGFR1, such as FGF2. Approximately half of the 22 known FGFs can activate FGFR1, leading to increased FGF signaling and cancerous cell growth. Another function of FGF proteins and their receptors is to mediate the growth of blood vessel tissue. This process, known as angiogenesis, can accelerate the growth of tumors by increasing the supply of oxygen and other nutrients available to the cancer cells.
As a ligand trap, FP-1039 is thought to bind to FGF ligands circulating in the extracellular space, thereby preventing these signaling proteins from reaching FGFR1 on the surface of tumor cells where they would otherwise stimulate cancer cell division and/or angiogenesis. However, FP-1039 is not believed to bind to certain "hormonal" FGFs, including FGF23, which regulates phosphate levels in the blood. As a result, treatment with FP-1039 has not been shown to cause hyperphosphatemia, a side effect seen with small molecule inhibitors of FGF receptors, which block the activity of both cancer-associated FGFs and FGF23.
Mesothelioma is a disease with high unmet medical need and high mortality rate. A majority of mesothelioma patients have tumors with abnormally high levels of FGF-2. In preclinical testing, we observed inhibition of mesothelioma tumor growth with single-agent FP-1039. Mesothelioma is an orphan indication in the United States with a prevalence of about 4,000 patients and incidence of about 3,000 patients. Worldwide, there are a total of approximately 14,000 cases of mesothelioma diagnosed each year.
Five Prime’s former partner for FP-1039, GlaxoSmithKline (GSK), conducted and funded a Phase 1b trial of FP-1039 in patients with Malignant Pleural Mesothelioma (MPM). The MPM arm of the study evaluated the safety and efficacy of FP-1039 (IV weekly) in combination with standard pemetrexed + cisplatin. The study design involved dose escalation until maximum tolerated dose (MTD) followed by a cohort expansion phase. Endpoints included safety, overall response rate by modified RECIST 1.1, disease control rate (DCR), progression free survival (PFS) and exploratory translational objectives. Data from this trial will be presented at the 2017 ESMO Annual Meeting.
Five Prime holds worldwide rights for FP-1039.